Molecular alterations associated with metastases of solid pseudopapillary neoplasms of the pancreas.

Eliana Amato,Giuseppe Zamboni,Pietro Delfino,Katarzyna Sikora,Borislav Rusev,Michele Simbolo,Vincenzo Corbo,Elisabetta Sereni,Giovanni Marchegiani,Antonio Pea,Stefano Barbi,Kenichi Hirabayashi,Matteo Fassan,Maria Ballotta,Günter Klöppel,Davide Antonello,Caterina Vicentini,Nobuyuki Ohike,Aldo Scarpa,Andrea Mafficini,Laura Maggino,Laura D Wood ,Irene Espósito ,Rita T Lawlor

doi:10.1002/path.5180

Abstract

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Highlights

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare low-grade malignant neoplasm that usually occurs in young women [1]
We found that clinically benign SPNs have diploid genomes and no relevant copy-number variation (CNV), whereas one case with features of malignancy, including cellular atypia and high proliferative index associated with necrosis, showed loss of heterozygosity (LOH) on chromosome 21
In our cohort of SPNs, we found that a lack of or reduced expression of both KDM6A and BAP1 is enriched in metastatic cases, suggesting that their function is a barrier to the development of metastatic disease at least in a subset of SPNs

Summary

Introduction

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare low-grade malignant neoplasm that usually occurs in young women [1]. SPN is composed by polygonal cells that form a solid and pseudopapillary pattern, where they become discohesive. SPN has a peculiar immunophenotype among primary pancreatic neoplasms, which encompasses the expression of the mesenchymal marker vimentin, the protease inhibitor α1-anti-trypsin, the neuroendocrine marker neuron-specific enolase [1], progesterone receptors, CD10, CD56, cyclin D1 and claudins 5 and 7 [2]. The majority of SPNs are confined to the pancreas, with metastases to the liver and peritoneum in up to 15% of cases [1]. SPN has an indolent clinical behaviour even for cases of large tumour size, and long-term prognosis following surgical resection is generally excellent for both localised and distant disease [3]

Methods

Results

Conclusion